Several Research Avenues Are Available for Improving Response to Immunotherapy in Advanced NSCLC

Tony S.K. Mok, MD, BMSc, FRCPC, FASCO

Tumor treating fields (TTFields), dual checkpoint inhibition, cancer vaccines, and microbiome manipulation have the potential to improve the trajectory of responses with immunotherapy in non–small cell lung cancer (NSCLC), but more research and time are needed to determine whether they have a future in the armamentarium, according to Tony S.K. Mok, MD, BMSc, FRCPC, FASCO.

Mok, the Li Shu Fan Medical Foundation Professor of Clinical Oncology at The Chinese University of Hong Kong in China, highlighted data on TTFields, other novel immunotherapy partners, and potential new immunotherapy approaches in the treatment of patients with NSCLC in a presentation delivered during the 24th Annual International Lung Cancer Congress.¹

The phase 3 LUNAR trial (NCT02973789) investigated TTFields, which are electric fields that apply physical forces on electrically charged components in dividing cancer cells, causing an antimitotic effect. Downstream effects include cell stress–induced immunogenic cell death, resulting in a systemic antitumor immune response.²

To be eligible for enrollment in the trial, patients had to be at least 22 years of age with metastatic NSCLC and progression on or after platinum-based chemotherapy. A total of 276 patients were randomly assigned to receive TTFields plus standard of care (SOC) consisting of investigator’s choice immune checkpoint inhibitor or docetaxel, or SOC alone. Patients underwent follow-up every 6 weeks via CT scan until progression. The trial was positive, with a median overall survival (OS) of 13.2 months (95% CI, 10.3-15.5) with TTFields vs 9.9 months (95% CI, 8.1-11.5) with SOC alone (HR, 0.74; 95% CI, 0.56-0.98; P = .035).

However, the benefit was seen in the intention-to-treat population, so it’s not clear which group of patients truly benefits. When broken down by treatment, investigators observed limited benefit with TTFields in the patients who received second-line docetaxel (HR, 0.81; 95% CI, 0.55-1.19; P = .26) vs those who received a second-line immune checkpoint inhibitor (HR, 0.63; 95% CI, 0.41-0.96; P = .03). “The difference in OS outcome is driven by the immune checkpoint inhibitor subgroup, but second-line immunotherapy is no longer a SOC given the general use of first-line immunotherapy,” Mok said.

Moreover, 49% and 38% of patients in the TTFields and SOC arm, respectively, had unknown PD-L1 status, leaving a question mark as to whether PD-L1 expression was truly balanced between arms.

“Imbalance of PD-L1 status in the immune checkpoint inhibitor [cohort] could have attributed to the difference in OS,” Mok said. “The LUNAR study met the primary end point of OS, but TTFields is not yet a standard partner for second-line immune checkpoint inhibition.”

Antibody-drug conjugates have generated significant interest alone, but Mok said he was unsure of their compatibility with immunotherapy. Datopotamab deruxtecan (Dato-DXd) was evaluated in combination with pembrolizumab (Keytruda) and platinum-based chemotherapy in patients with advanced or metastatic NSCLC in the phase 1 TROPION-Lung02 study (NCT04526691). The objective response rate (ORR) with the doublet and triplet was 38% (95% CI, 26%-51%) and 49% (95% CI, 37%-61%), respectively. In the frontline setting, response rates increased to 50% (95% CI, 32%-68%) and 57% (95% CI, 42%-70%), respectively. In the frontline setting, the median duration of response was not evaluable (NE) with either the doublet or triplet regimen.³

Further studies including the TROPION-Lung07 (NCT05555732) and TROPION-Lung08 (NCT05215340) trials will evaluate the combination of Dato-DXd and pembrolizumab in larger, phase 3 trials.

“[We’ve shown] feasibility with combining an anti–Trop-2 ADCs with pembrolizumab, [and we may be] ready to conjugate pending phase 3 trials,” Mok said.

Since the approval of nivolumab (Opdivo) and ipilimumab (Yervoy), excitement for dual checkpoint inhibition has fallen behind that for chemoimmunotherapy regimens. The ongoing SKYSCRAPER trials have the potential to revive enthusiasm for dual checkpoint inhibition, but it’s too early to tell they will revitalize these efforts following an initial report that the phase 3 SKYSCRAPER-01 trial (NCT04294810) failed to meet its primary end point of progression-free survival improvement with atezolizumab (Tecentriq) and tiragolumab vs atezolizumab alone Mok said.⁴ However, significant investment has already been made in this arena, Mok added, citing over 15 ongoing trials evaluating with dual checkpoint inhibition. “Dual checkpoint inhibitor combinations are at risk,” Mok said.

Additionally, several PD-1 inhibitors, which are approved in China, may be worth considering given their substantial price cut from approved PD-1/PD-L1 inhibitors in the United States. Mok highlighted toripalimab in particular, which was evaluated in combination with pemetrexed and platinum-based chemotherapy vs chemotherapy alone in patients with advanced, treatment-naïve NSCLC in China in the phase 3 CHOICE-01 trial (NCT03856411).⁵

The study results demonstrated a significant improvement in OS with the addition of toripalimab vs chemotherapy alone, with medians of 23.8 months (95% CI, 21.2-27.8) and 17.0 months (95% CI, 14.4-21.9), respectively (HR, 0.73; 95% CI, 0.57-0.93; P = .0108). The study, though not conducted in the United States, mirrored the pivotal, phase 3 KEYNOTE-189 trial (NCT02578680), which demonstrated an improvement in progression-free survival (HR, 0.48; 95% CI, 0.40-0.58) and OS (HR, 0.56; 95% CI, 0.45-0.70) with pembrolizumab plus chemotherapy vs chemotherapy alone.

Regarding new approaches, Mok pointed to cancer vaccines, a “conceptually sound” approach that is beginning to build a body of clinical data supporting its use. In the phase 3 ATALANTE-1 trial (NCT02654587), OSE-2101 was evaluated vs SOC docetaxel or pemetrexed in patients with HLA-A2–positive, advanced or metastatic NSCLC who disease had progressed on immune checkpoint inhibitors. The results showed a substantial improvement in OS with OSE-2102 (n = 80) vs SOC (n = 38; HR, 0.59; 95% CI, 0.38-0.91; P = .017). Median OS was 11.1 months (95% CI, 8.6-13.5) with OSE-2101 vs 7.5 months (95% CI, 4.7-10.3) with SOC.⁶

mRNA vaccines are also under study, Mok said, with some having shown enhanced CD8 T-cell responses following vaccination in preclinical studies. A phase 1 study (NCT03948763) evaluated mRNA-5671 (V941) as monotherapy and in combination with pembrolizumab in patients with KRAS-mutant advanced or metastatic NSCLC, and other solid tumors. Notably, patients were selected for the HLA subtypes most likely to respond.

Another category of cancer vaccines that have received attention is neoantigen-based personalized vaccines such as mRNA-4157 (V940), which has the advantage of being able to target an individual patient’s unique tumor mutations through integrated manufacturing. “Cancer vaccines are under rapid development, especially the concept of personalized vaccines,” Mok said.

This specific vaccine is being studied in combination with pembrolizumab in patients with advanced cutaneous melanoma following complete surgical resection in the randomized, phase 2 KEYNOTE-942 trial (NCT03897881). To be eligible for enrollment, tissue must be available for next-generation sequencing. Preliminary results have shown that the addition of the vaccine to pembrolizumab led to an improvement in recurrence-free survival vs pembrolizumab alone regardless of PD-L1 status (HR, 0.561; 95% CI, 0.309-1.017; P =.0266).⁷

Finally, Mok highlighted the potential for fecal transplant to broaden the use of immune checkpoint inhibitors. In a study presented at the 2023 ASCO Annual Meeting, a fecal microbiota transplant combined with PD-1 inhibition led to 1 partial response among 13 patients with immune-refractory, unresectable or metastatic solid tumors. “Fecal transplantation may modify immune response, but specification may be required,” Mok concluded.

Editor’s note: Dr Mok reported receiving grant/research support from AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals, Roche, Merck Sharp & Dohme, Clovis Oncology, Bristol Myers Squibb, Eisai, and Taiho; speaker fees from AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, and Taiho; being a major shareholder in Sanomics Ltd; serving on an advisory board for AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, Merck Serono, Merck Sharp & Dohme, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Vertex Pharmaceuticals, Bristol-Myers Squibb, geneDecode, OncoGenex, Celgene, Ignyta, Cirina; and serving on the board of directors for the International Association for the Study of Lung Cancer (IASLC), Chinese Lung Cancer Research Foundation Ltd., AstraZeneca; HutchMed, and ACT.

References

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